Submissions for variant NM_001182.5(ALDH7A1):c.834G>A (p.Val278=)

gnomAD frequency: 0.00004  dbSNP: rs201948406

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255917	SCV000321394	pathogenic	not provided	2023-07-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, suggesting this variant leads to abnormal gene splicing (Salomons et al., 2007); This variant is associated with the following publications: (PMID: 23022070, 22529283, 20554659, 19128417, 24122892, 17721876, 26026794, 27438048, 27324284, 23430810, 28973083, 29852413, 24748525, 20814824, 30043187, 31589614, 35782612, 31440721)
Invitae	RCV000019618	SCV000640330	pathogenic	Pyridoxine-dependent epilepsy	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change affects codon 278 of the ALDH7A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ALDH7A1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs201948406, gnomAD 0.01%). This variant has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 17721876, 19128417, 20554659, 20814824, 22529283, 23022070, 23430810, 24122892, 27438048). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.750G>A. ClinVar contains an entry for this variant (Variation ID: 18002). Studies have shown that this variant results in cryptic splice site activation and introduces a premature termination codon (PMID: 17721876). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000255917	SCV000703760	pathogenic	not provided	2016-12-27	criteria provided, single submitter	clinical testing
Elsea Laboratory, Baylor College of Medicine	RCV000019618	SCV001424278	pathogenic	Pyridoxine-dependent epilepsy	2020-04-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433461	SCV002678553	likely pathogenic	Inborn genetic diseases	2018-01-31	criteria provided, single submitter	clinical testing	The c.834G>A variant (also known as p.V278V), located in coding exon 9, results from a G to A substitution at nucleotide position 834 of the ALDH7A1 gene. This nucleotide substitution does not change the amino acid at codon 278. This nucleotide position is well conserved in available vertebrate species. This alteration has been detected in the homozygous and compound heterozygous state with other ALDH7A1 variants in several individuals with diagnoses of pyridoxine-dependent epilepsy (PDE) (Salomons GS et al. Ann. Neurol., 2007 Oct;62:414-8; Mercimek-Mahmutoglu S et al. Pediatrics, 2012 May;129:e1368-72; Proudfoot M et al. JIMD Rep, 2013 Mar;10:103-6; Coughlin CR et al. Mol. Genet. Metab. May;116:35-43; Yuzyuk T et al. Mol. Genet. Metab., 2016 07;118:167-72). In one study, authors isolated RNA from a homozygous individual to show that this alteration preferentially uses a cryptic donor splice site resulting in an out of frame deletion in exon 9 which leads to the p.Val250Glyfs*23 frameshift (Salomons GS et al. Ann. Neurol., 2007 Oct;62:414-8). Of note, this alteration is often called p.V250V (c.750G>A) in the literature. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to create a new alternate splice donor site, but BDGP does not predict the creation of a non-native donor site, nor a deleterious effect on splicing; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genome-Nilou Lab	RCV000019618	SCV004049190	likely pathogenic	Pyridoxine-dependent epilepsy	2023-04-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000019618	SCV004242018	pathogenic	Pyridoxine-dependent epilepsy	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: ALDH7A1 c.834G>A alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Salomons_2007). The variant allele was found at a frequency of 5.6e-05 in 251486 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ALDH7A1 causing Pyridoxine-Dependent Epilepsy (5.6e-05 vs 0.0018), allowing no conclusion about variant significance. c.834G>A (also known as c.750G>A. ) has been reported in the literature in multiple individuals affected with Pyridoxine-Dependent Epilepsy (examples: Salomons_2007 and Marguet_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17721876, 27438048). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000019618	SCV000039916	pathogenic	Pyridoxine-dependent epilepsy	2007-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000019618	SCV001775554	not provided	Pyridoxine-dependent epilepsy		no assertion provided	literature only	The 2nd most common pathogenic variant, accounting for 5.4% of pathogenic variants